Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus

Официальное название

Randomized Pilot Trial to Evaluate the Efficacy and Tolerance of Abacavir/Lamivudine Treatment in Patients With Systemic Lupus Erythematosus (PENCIL)

Обзор

Systemic lupus (SL) is a rare chronic autoimmune disease characterized by the production of autoantibodies directed against nuclear antigens, particularly native double-stranded deoxyribonucleic acid (DNA), and excessive production of antiviral cytokines: type I interferons, particularly interferon alpha (IFN-α). IFN-α production results from the excessive detection of nucleic acids (DNA or Ribonucleic Acid (RNA)) by endosomal or intracytoplasmic receptors that are capable of inducing interferon production. The precise mechanisms of cytoplasmic sensor activation remain unknown; however, recent work in the field of interferonopathies suggests a role for human endogenous retroviruses (HERVs). HERVs are remnants of ancient infections caused by exogenous retroviruses integrated into the genome during evolution and represent 8% of the human genome.Several studies have suggested a role for HERVs in the development and maintenance of an excessive immune response in lupus patients and other autoimmune diseases by affecting the type I interferons (I IFN) signalling pathway. To date, none of the approved immunosuppressive drugs for Systemic Lupus Erythematosus (SLE) have been shown to be effective in the background treatment of SL or in preventing relapse. Consequently, there is an urgent need to identify new molecules and therapeutic avenues for disease-modifying therapies. In this study, an innovative therapeutic strategy using a combination of nucleoside reverse transcriptase inhibitors (NRTIs), abacavir/lamivudine, is proposed to treat SLE. Thus, we propose a pilot Phase II, randomized, open-label study using NRTIs in patients with SL in remission or with low clinical activity, and evaluating a biological endpoint (IFN signature), which is a direct proxy for the drug's expected effect. The main objective is to compare the addition of Abacavir/Lamivudine (Add-on) to standard care for 6 months, on the value of the interferon (IFN) transcriptomic signature of patients with systemic lupus with low activity as defined by the Lupus Low Disease Activity State (LLDAS).

Вмешательства

• Биопрепарат Blood sample
  blood test to assess : * human leukocyte antigen (HLA)-B\*5701 status to identify risk of allergy or hypersensitivity to abacavir (the study treatment) * IFN-signature ans IFN-alpha dosage * human immunodeficiency virus (HIV), hepatitis B virus (HBV) and Hepatitis C virus (HCV) serologies * Human chorionic gonadotropin (βHCG) * HERVs dosage A biological collection will also be created. The total volume of blood collected specifically for the research for the entire duration of the study is 62.5
• Препарат Treatment :Abacavir 600 mg/lamivudine 300 mg
  Patients randomised to the experimental arm will be required to take 1 tablet (600 mg lamivudine and 300 mg abacavir) once daily for 6 months in addition to their usual treatment.
• Другое Lupus Impact Tracker questionnaire
  Patients will be asked to complete the Lupus Impact Tracker questionnaire at visit V1 (randomisation visit), visit 3 (at 6 months of treatment) and visit 4 (12 months after visit 1).

Первичные конечные точки

• Absolute variation in interferon signature (IFN) [Срок оценки: At M6 (after 6 months of treatment)]

Вторичные конечные точки (12)

• percentage of patients maintaining LLDAS criteria [Срок оценки: until 12 months after randomisation]
• number of relapses [Срок оценки: until 12 months after randomisation]
• anti-native double-stranded DNA quantification [Срок оценки: until 12 months after randomisation]
• anti-extractable nuclear antigens (anti-ENA) quantification [Срок оценки: until 12 months after randomisation]
• interferon-α production quantification [Срок оценки: until 12 months after randomisation]
• Number of successful patients [Срок оценки: until 6 months after randomisation]
• Cumulative dose of intravenous (IV) corticosteroids [Срок оценки: until 12 months after randomisation]
• Lupus Impact Tracker questionnaire score [Срок оценки: until 12 months after randomisation]
• number of missed treatment [Срок оценки: until 6 months after randomisation]
• number of adverse event (AE) [Срок оценки: until 12 months after randomisation]
• number of serious adverse event (SAE) [Срок оценки: until 12 months after randomisation]
• HERVs transcription quantification [Срок оценки: until 12 months after randomisation]

Критерии участия

Критерии включения

• Patient ≥12 years old (weighing more than 25 kg) and ≤ 65 years old
• Diagnosis of SL according to 2019 American College of rheumatology (ACR) / European Ligue against Rheumatism (EULAR) criteria (score >10)
• Patient with SL in remission or with low clinical activity according to LLDAS disease criteria
• For patients (including sexually active adolescents) of childbearing age, effective contraception (sexual abstinence, hormonal contraception, intrauterine device or hormone-releasing system, cap, diaphragm, sponge with spermicide, or condom) for the entire duration of treatment is required. Pregnancy tests will be performed according to the inclusion criteria.
• Patient affiliated to a social security scheme
• Free, informed and written consent signed by patient or parents/legal guardian

Критерии исключения

• Patients with HLA-B\*5701 status (risk of allergy or hypersensitivity to Abacavir)
• History of allergy or hypersensitivity to abacavir, lamivudine, or excipients (tablet core: microcrystalline cellulose, crospovidone, magnesium stearate, colloidal anhydrous silica, talc; film coating: hypromellose, titanium dioxide (E171), macrogol, polysorbate 80).
• Patients on anti-retroviral therapy
• Patients with chronic HIV, HBV or HCV infection
• Pregnant or breast-feeding woman
• Patient treated with Lamivudine and/or Abacavir
• Patient treated with a cytidine analog
• Patient on treatment containing Cladribine
• Patient on treatment containing a trimethoprim/sulfamethoxazole combination
• Patients with renal insufficiency (creatinine clearance < 50 ml/min)
• Patients with moderate or severe hepatic impairment (prothrombin level <50%)
• Patient participating in other interventional drug research

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 11 центров

• Groupe Hospitalier Pellegrin-CHU de Bordeaux — Bordeaux
• Hôpital Femme-Mère-Enfant (HCL) — Bron
• CHU de Clermont-Ferrand - Hôpital Gabriel Montpied — Clermont-Ferrand
• CHU Nord de Grenoble - Albert Michallon — Grenoble
• Hôpital Claude Huriez — Lille
• Hôpital de la Croix-Rousse (HCL) — Lyon
• Hôpital Edouard Herriot (HCL) — Lyon
• Hôpital Necker-Enfants malades — Paris
• … и ещё 3 центра

Идентификаторы

NCT: NCT06356740 · 69HCL22_0878 · 2023-508611-22-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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